When should ovarian and adrenal causes of hyperandrogenism be considered in patients?

When to Consider Ovarian and Adrenal Causes of Hyperandrogenism

Suspect ovarian or adrenal tumors when testosterone levels are markedly elevated (typically >150-200 ng/dL), symptoms develop rapidly (over weeks to months rather than years), or virilization is present—these features warrant urgent imaging and potentially surgical evaluation. 1

Red Flag Clinical Features Requiring Tumor Evaluation

Severe Biochemical Hyperandrogenism

• Very high testosterone levels (>150-200 ng/dL) strongly suggest an androgen-secreting tumor rather than PCOS, which typically causes only mild-to-moderate elevations 1, 2
• Markedly elevated DHEAS levels point toward an adrenal source of androgen excess 3, 1
• When both testosterone and DHEAS are significantly elevated, consider the possibility of adrenocortical carcinoma, which can secrete multiple hormones 3

Rapid Onset and Virilization

• Virilization signs—including clitoromegaly, deepening voice, male-pattern baldness, and increased muscle mass—indicate severe androgen excess that is rarely seen with PCOS and should prompt immediate evaluation for ovarian or adrenal tumors 3, 1
• Symptoms developing over weeks to months (rather than the gradual onset typical of PCOS starting after menarche) suggest a tumor 4, 2
• Androgen-secreting tumors in women may induce hirsutism, deepening of the voice, and oligo/amenorrhea 3

Age-Related Considerations

• Postmenopausal hyperandrogenism is particularly concerning, as PCOS does not present de novo after menopause—new-onset hyperandrogenism in this population warrants aggressive evaluation for ovarian hyperthecosis or androgen-secreting tumors 5, 4, 6
• In postmenopausal women, even moderate testosterone elevations with virilization should trigger imaging and consideration of bilateral salpingo-oophorectomy 5, 4

Diagnostic Algorithm for Source Localization

Initial Laboratory Assessment

• Measure total testosterone by LC-MS/MS and DHEAS to help differentiate ovarian from adrenal sources 3, 1
• DHEAS >700 μg/dL suggests an adrenal source, while isolated testosterone elevation points toward ovarian pathology 3, 1
• Perform 1 mg overnight dexamethasone suppression test: failure to suppress testosterone suggests an autonomous tumor (ovarian or adrenal), while suppression of DHEAS but not testosterone indicates ovarian source 5, 2

Imaging Strategy

• CT or MRI of abdomen and pelvis should be performed when tumor is suspected based on clinical or biochemical features 3
• For adrenal masses, assess Hounsfield units (HU): ≥10 HU on non-contrast CT raises concern for pheochromocytoma or malignancy and requires further evaluation 3
• Adrenal tumors >5 cm, inhomogeneous, with irregular margins or local invasion suggest adrenocortical carcinoma 3
• Ovarian tumors causing hyperandrogenism are often too small to visualize on standard imaging, even when clinically significant 4, 6

Advanced Localization When Imaging is Inconclusive

• GnRH analogue suppression testing can differentiate ovarian from adrenal sources: suppression of testosterone after GnRH analogue administration confirms gonadotropin-dependent ovarian androgen production 6
• Adrenal and ovarian vein sampling is technically challenging but can definitively localize the source when imaging is non-diagnostic 5, 6
• In postmenopausal women with confirmed ovarian source and normal imaging, bilateral salpingo-oophorectomy serves as both diagnostic and therapeutic intervention 5, 4, 6

Specific Tumor Considerations

Adrenal Tumors

• Approximately 60% of adrenocortical carcinomas present with hormone excess, often with virilization 3
• Suspect malignancy if the adrenal tumor is >3 cm for aldosterone-secreting or >5 cm for cortisol-secreting lesions, has irregular morphology, is lipid-poor, or doesn't wash out on contrast-enhanced CT 3
• Cushing syndrome features (weight gain, proximal weakness, hypertension, purple striae, buffalo hump) alongside hyperandrogenism suggest adrenal pathology 3

Ovarian Tumors

• Ovarian androgen-secreting tumors (Leydig cell tumors, hilus cell tumors, Sertoli-Leydig cell tumors) are typically small (<2 cm) and may not be visible on imaging 5, 4, 6
• Ovarian hyperthecosis—a benign condition causing hyperandrogenism—is strongly associated with insulin resistance and metabolic syndrome in postmenopausal women 4
• When ovarian source is confirmed but imaging is negative, laparoscopic bilateral salpingo-oophorectomy is both diagnostic and curative 5, 4, 6

Common Pitfalls to Avoid

• Don't assume PCOS in postmenopausal women—PCOS does not present de novo after menopause, and new hyperandrogenism requires tumor exclusion 4, 6
• Don't rely solely on imaging—many functional ovarian tumors are below the resolution of current imaging modalities 4, 6
• Don't delay evaluation when virilization is present—this always warrants urgent investigation regardless of age 3, 1, 2
• Don't forget to screen for pheochromocytoma in patients with adrenal masses ≥10 HU, as these can co-secrete androgens 3
• Consider non-classic congenital adrenal hyperplasia (NCCAH) in younger women with moderate hyperandrogenism—measure 17-hydroxyprogesterone and perform ACTH stimulation testing if elevated 1, 2